Compositions of tocol-soluble therapeutics

ABSTRACT

Tocol-based compositions of charged amphiphilic and water soluble pharmaceutically active compounds or their charged precursors are prepared by forming a tocol-soluble ion pair with an oppositely charged ion-pair forming compound capable of forming a tocol-soluble ion-pair with the active compound.  
     Also disclosed are novel compounds tocopherolsuccinate-aspartate and tocopherolsuccinate-glutamate, which are useful as ion-pair forming compounds.

BACKGROUND AND PRIOR ART

[0001] The invention is directed to compositions having an oil phasethat contains pharmaceutically active ingredients that are chargedamphiphilic or water soluble. The compositions generally comprisetocol-soluble ion pairs in a tocol-based oil of a multiphasic system ora precursor of such a system. The compositions of the invention can bein the form of an emulsion, liquid crystalline gel, self-emulsifyingdrug delivery system, or a liposomal or niosomal dispersion for oral orparenteral administration, which term is meant to include, for instance,intravenous, subcutaneous, intraperitoneal, intramuscular, pulmonary,intranasal, and topical administration such as transdermal and ocular.Emulsions or microemulsions and self-emulsifying drug delivery systemsare the preferred form of the compositions of the present invention.

[0002] Emulsions, and emulsification as a composition and method ofadministration of pharmaceuticals, have a long history in the medicalarts. A recent advance was the use of α-tocopherol or other tocopherols,tocotrienols or derivatives thereof as a solvent to dissolve certaindrugs at high enough concentrations to be therapeutically useful. TPGS(α-tocopherol polyethyleneglycol 1000 succinate) for administration of atherapeutic was claimed by Biogal (U.S. Pat. No. 5,583,105) followingdisclosure in trade publications of the utility of TPGS as abioavailability enhancer for drug delivery (Sokol, et al. The Lancet338:212-215, 1991). Vitamin E and tocopherol acetates and succinates,including TPGS, were recently found useful in pharmaceuticalformulations as solubilizers and co-solvents for the administration ofmedicaments (Dumex WO/95,31217 and Liposome Company, U.S. Pat. No.5,041,278). Other patents disclose that tocopherols are excellentsolvents for the peptide cyclosporin (Klokkers WO 95/11039), and forcertain steroids (Peat, U.S. Pat. No. 4,439,432). Stillman (U.S. Pat.No. 4,551,332), and Hermes Pharma (EP 019817) described composition inwhich steroids and antibiotics, or ubiquinones, respectively, wereco-solubilized in Vitamin E as pharmaceutical formulations.

[0003] Subsequent disclosures by Sonus Pharmaceuticals (WO 98/30205);Sherman (WO 97/22358; WO 98/30204) and Danbiosyst (WO 97/03651; WO99/04787) expanded this new appreciation of tocopherols and tocotrienolsas a solvent for delivery of hydrophobic medicaments, particularly whencombined with TPGS, phospholipids, and certain co-solvents andemulsifiers.

[0004] The benefits of emulsions are several. In general, emulsificationcan lead to reduced toxicity when compared to aqueous solutions of thedrug. Extreme conditions of pH or ionic strength are required tosolubilize some drugs in aqueous solutions. Also, sustained release hasbeen observed from emulsions formed as a blood pool or intra-tissuedepot, from which the active agent is progressively released withdesirable increased efficacy or duration of treatment. In other cases, ahigh plasma peak concentration (Cmax) can be obtained without undue riskto the patient. Finally, the stability of selected drugs in the oilphase may be improved when compared to aqueous solutions of the samedrug. Emulsions in tocopherols, tocotrienols or derivatives thereof havethe added advantage that the emulsion itself may be therapeutic forcertain conditions.

[0005] However, only selected lipophilic active agents are highlysoluble in tocopherols and tocotrienols. Furthermore, lipophilic agentsthat are charged tend to remain associated with the water or plasma,where they may be subject to degradation, even while residing in part inthe oil phase. Finally, some water-soluble agents or amphiphilic agentsthat could benefit from the advantages of a tocopherol or tocotrienolformulation are not readily soluble in these oils.

[0006] It would thus be desirable to provide pharmaceutical compositionsin which a charged amphiphilic or water soluble active agent ispartitioned into the tocol oil phase of a multiphasic system.

[0007] One approach to improve the oil solubility of such ingredients isto covalently modify the active agent so as to render it morelipophilic. Fatty acid- or lipid-drug conjugates have been disclosed asa means of rendering water-soluble drugs more lipophilic, more readilyabsorbable through various mucosal membranes, such as the intestinal,corneal and dermal, and for targeting of drugs (NexStar U.S. Pat. Nos.6,024,977; 5,827,819; 5,543,389; 5,543,390; 5,840,674; 5,543,391;5,256,641; 5,149,794).

[0008] Another solution has been to use liposomes, reverse emulsions orwater/oil/water multiple emulsions, in which the drug may be containedin an aqueous phase dispersed in the oil matrix or, in the case ofliposomes, enclosed within a lipid bilayer. These formulations areparticularly valuable for water-loving drugs and macromolecules but maynot provide the advantages of solubilizing the drug directly in the oil.In addition there are physical stability considerations of such systems.

SUMMARY OF THE INVENTION

[0009] The invention comprises a pharmaceutical composition comprising atocol as a solvent and a tocol-soluble ion pair of two oppositelycharged compounds, one of the said compounds being a chargedpharmaceutically active agent or a charged precursor of the active agentand the other being an oppositely charged compound capable of forming atocol-soluble ion pair with the pharmaceutically active compound. Incases of multiply charged pharmaceutically active compounds orprecursors of charged pharmaceutically active compounds at least onecharge on the active agent is available for ion-pairing. The inventionalso relates to processes for preparing such compositions.

DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention is directed to formulations or compositionsof those drugs which are amphiphilic or water soluble by virtue ofhaving a substituent ionic charge, for example a cation formed from asecondary amine (a base), or an anion formed by dissociation of acarboxyl, phosphate or sulfate (an acid). These drugs may be renderedtocol-soluble by the formation of an ion-pair between the drug and anoppositely charged molecule. The active agent of the composition must bemore soluble in the tocol oil in the form of an ion pair than withoutit. Thus, formation of the ion-pair results in substantial improvementin the solubility of the active agent in the tocol oil.

[0011] To better aid in understanding the invention, the followingdefinitions are offered:

[0012] Tocopherols: tocopherols are a family of natural and syntheticcompounds. d-α-tocopherol, also known as Vitamin E, is the most familiarmember of this class of compounds and has the following chemicalstructure (Scheme I):

[0013] The molecule contains three structural elements, a chroman headwith a phenolic alcohol and a phytyl tail. Not all tocopherols havethree methyl groups on the chroman head. The simplest member of thisgroup, 6-hydroxy-2-methyl-2-phytylchroman contains no methyl groups onthe chroman ring, and is sometimes simply referred to as “tocol”.However, the terms “tocols” and “tocol” is used herein to represent abroader class of compounds. Other members of the tocopherol classinclude α-, β-, γ-, and δ-tocopherols and Trolox® (6-hydroxy,2,5,7,8-tetramethylchroman-2-carboxylic acid) and its desmethyl analogs.In addition to their use as a primary solvent, some tocopherols andtheir derivatives are useful as a therapeutic agents.

[0014] Tocotrienols: tocotrienols have structures related to thetocopherols but possess a 3,7,11 triene “tail”. The structure ofd-α-tocotrienol is shown in Scheme II.

[0015] Again, as is the case for the tocopherols, not all tocotrienolshave three methyl groups on the chroman head. There are four majortocotrienols, α-, β-, γ-, and δ-tocotrienols.

[0016] Tocols: “Tocols” is used herein in a broad sense to indicate thefamily of tocopherols and tocotrienols and derivatives thereof,including those common derivatives esterified at the 6-hydroxyl on thechroman ring. This use of the term “tocols” is appropriate since alltocopherols and tocotrienols are fundamentally derivatives of thesimplest tocopherol, 6-hydroxy-2-methyl-2-phytylchroman (sometimesreferred to as “tocol”).

[0017] Tocol-Soluble: Refers to the property of certain moleculescharacterized as being soluble directly, or with the aid of aco-solvent, in a tocol. As an operative definition, the most useful wayto determine tocol solubility is to dissolve the compound of interest ina tocol or to use a co-solvent such as ethanol.

[0018] Amphiphilic: A molecule that is both oil and water soluble.

[0019] Lipophilic: Literally, fat-loving, referring to the property ofcertain molecules characterized as soluble in triglyceride oils,hydrocarbons or waxes.

[0020] Ion Pair: A neutral pair formed between two oppositely chargedcompounds.

[0021] Tocol-Soluble Ion Pair: An ion pair formed between two oppositelycharged compounds and which is soluble in tocols.

[0022] Biocompatible: Capable of performing functions within or upon aliving organism in a manner that does not terminate or excessivelydisable the life of the organism, i.e. without undue toxicity or harmfulphysiological or pharmacological effects.

[0023] Multiphase System: As used herein, this term refers to a systemwhere one or more phases is (are) dispersed throughout another phase,which is usually referred to as the continuous phase or vehicle, or aprecursor thereof. Emulsions, microemulsions and other nanoparticulates,including liposomes and niosomes, are examples of multiphase systems.

[0024] Liposome: A lipid bilayer vesicle formed spontaneously upondispersion of lipids/phospholipids in water. “Liposome” is also definedas a vesicular structure consisting of hydrated bilayers.

[0025] Niosome: In analogy to a liposome, a niosome is a nonionicsurfactant vesicle. Classes of commonly used non-ionic surfactantsinclude polyglycerol alkylethers, glucosyl dialkylethers, crown ethersand polyoxyethylene alkyl ethers and esters.

[0026] Micelle: Organized aggregates of one or more surfactants insolution.

[0027] Emulsion: A colloidal dispersion of two immiscible liquids, suchas oil and water, in the form of droplets. The internal phase is alsotermed the dispersed phase and the external phase is termed thecontinuous phase. The mean diameter of the dispersed phase, in general,is between about 0.1 and about 5.0 microns, as is commonly measured byparticle sizing methods. Emulsions in which the dispersed phase andcontinuous phase have different refractive indexes are typicallyoptically opaque. Emulsions possess a finite or limited stability overtime, and can be stabilized by the incorporation of amphiphilicexcipients known as surfactants and by viscosity modifiers.

[0028] Microemulsion: A thermodynamically stable, isotropically cleardispersion of two immiscible liquids, stabilized by an interfacial filmof surfactant molecules. Microemulsions have a mean droplet diameter ofless than about 200 nm, in general between about 10-100 nm and aretypically self-assembling.

[0029] Tocol microemulsion: A thermodynamically stable, translucent orclear dispersion of a tocol oil in water, stabilized by an interfacialfilm of surfactant molecules. Tocol microemulsions have a mean dropletdiameter of less than about 200 nm, in general between about 50 andabout 100 nm, and typically are not self-assembling, but require heat orincreased shear to assemble due to the high viscosity of the tocol oil.

[0030] A highly preferred form of the invention for drug delivery is a“tocol microemulsion”. These vehicles for drug delivery are translucentand isotropic, of small mean droplet diameter, preferably less thanabout 150 nm, even more preferably less than about 100 nm, and mostpreferably from about 30 to 90 nm. They possess high drug solubilizationcapacity (a relative measure for each individual drug), and mostcharacteristically have extended or indefinite stability on storage byvirtue of their thermodynamic stability, which is preferably greaterthan 1 year, even more preferably greater than two years or more. Themicroemulsions of the current invention have a surfactant to oil ratioof about 1:1 to 1:5, preferably from about 1:1 to 1:2 and are frequentlyformulated with one or more co-solvents or co-surfactants to improveprocessing. Unlike vegetable oil microemulsions, which formspontaneously, tocol microemulsions are formed by homogenization in ahigh-shear device because of the extremely high viscosity of theseexcipients. However, once formed, they are essentially transparent ortranslucent, and highly stable. They preferably exhibit no particle sizegrowth over a typical pharmaceutical shelf life of one year or more.

[0031] Self-Emulsifying Drug Delivery Systems (SEDDS):

[0032] In the absence of an aqueous phase, mixtures of oil(s) andnon-ionic surfactant(s) form clear and isotropic solutions that areknown as self-emulsifying drug delivery systems (SEDDS). They havesuccessfully been used to improve lipophilic drug dissolution and oralabsorption. Such systems are essentially precursors of emulsion-typemultiphasic systems.

[0033] Active Agent: A compound or precursor thereof, natural orsynthetic, with an established therapeutic/pharmacological activity inanimals and humans. Relevant to this invention are compounds that arerelatively soluble in tocols and compounds that are relatively insolublein tocols.

[0034] Polyelectrolyte: A natural or synthetic molecule with multipleionizable groups. A polyelectrolyte can have multiple anions, multiplecations or a combination of both. Examples include peptides,polypeptides, proteins, saccharides and polysaccharides, polynucleotidesand nucleic acids.

[0035] Pharmaceutically active ingredients that may be employed in thecompositions of this invention are those that are charged amphiphilic orwater soluble. These include, for instance, therapeutic amines or bases,acids and zwitterions. Preferred classes of compounds include carboxylicacids, polycarboxylic acids, amines, polyamines, peptides, polypeptides,proteins, nucleosides, nucleotides, polynucleotides, saccharides,polysaccharides, polymers, and other charged polyelectrolytes. Mostpreferred are amines, peptides and polypeptides.

[0036] Some examples of preferred active ingredients for use in thisinvention are macrolide antibiotics such as clarithromycin anderythromycin, anthracycline antibiotics such as doxorubicin anddaunorubicin, camptothecin and its analogs (such as camptothecin,topotecan, irenotecan and derivatives thereof), quinolone antibioticssuch as ciprofloxacin, clinafloxacin, levofloxacin and moxifloxacin,amiodarone and its analogs, angiotensin-converting enzyme (ACE)inhibitors such as enalapril, enalaprilat, linosopril and their analogs,biogenic amines such as histamine, serotonin, tryptophane, epinephrineand analogs or derivatives thereof, the antineoplastics mitomycin andbleomycin and their analogs, and vincristine, nitrogen mustards, andnitrosourea and their analogs. Other chemotherapeutic agents may beused, as may antibiotics (antiviral, antibacterial, antihelminthic,antiplasmodial, or antimycotic), analgesics and local anesthetics,antidepressants anxietolytics, anti-psychotics, sedatives, hypnotics,hormones, steroids, cytomedines or cytokines, anti-histamines,anti-allergics, steroids, vaccine adjuvants and epitopes,immunosuppressive agents, vascular tonics, coronary drugs, vasodilators,anti-arrhythmics such as amiodarone, calcium antagonists, cardiacglycosides, antidotes, non-steroidal anti-inflammatory drugs,oligonucleotides, oligopeptides, anti-emetics, motion sickness drugs,and migraine therapeutics.

[0037] Specific examples of active ingredients that may be used in thecompositions of this invention include dihydroergotamines, epinephrine,adenosine, hydralazine, pipamazine, pyridoxine, prednimustine,propanolol, phenobarbital, arniodarone, miconazole, secobarbital,trimethoprim sulfamethoxazole, cytarabine, amphotericin B, diltiazem,verapamil, diazoxide, ketorolac, pentobarbital, phenyltoin, esmolol,capsaicins, oxytetracycline, chlorodiazepoxide, dimenhydrinate,benzodiazepines such as diazepam, fenoldopam, nitrazepam, flurazepam,lorazepam, estazolam, flunitrazepam, triazolam, alprazolam, midazolam,ternazepam, lermetazeparn, brotizolam, clobazam, oxazepam, clonazepam,thiethylperazine, nicardipine, haloperiodol, tobramycin, ciprofloxacin,clinafloxacin, levofloxacin, moxifloxacin, fluoxetine, metronidazole,doxepin, doxycycline, chloramphenicol, acyclovir, idoxuridine,dynorphine, tromantadine, tranylcypromine, meconazole, nystatin,metronidazole, tinidazol, diclofenac, piroxicam, morphine, Selegiline,lidocaine, buprenorphine, buspirone, metoclopramide, granisetron,tropisetron, ondansetron, chonemorphine, cinnarizine, ceftriaxone,eprosartan, ganciclovir, betamethasone acetate, methylprednisoloneacetate, prednisolone, sumatriptan, hydrocortisones, ibuprofen,methocarbamol, resveratrol, retinoids, carotenoids, tamoxifen,decarbazine, lonidamine, piroxantrone, chloroquine, streptomycin,kanamycin, gentamycin, dehydrostreptomycin, amikacin, chloropromazine,imipramin, suramin, perhexilene, methotrexate, sulmazol, leupeptin,methylamine, colchicine, pyridoxine, acetaminophen, desipramine,biperiden, dibenzepine, alprenolol, opipramol, propranolol,chlorpheniramine, clonixin, desipramine, n-acetyldesipramine,imipramine, chlomipramine, amitryptyline, sertraline, perazine,thioridazine, carbamazepine, promazine, amantadine, memantine,isoproterenol, methadone, lignocaine, pentacaine, nalorphine,trimetazidine, morphine-6-O-β-d-glucuronide, sulmazol, andphenothiazine.

[0038] Compositions of this invention containing tocol-soluble ion pairsare useful to formulate and deliver biogenic amines or their amino acidor peptide precursors. Biogenic amines are those cell signaling ortransmitter molecules produced by the body which contain a free amine.In some cases the precursor is also efficacious, for example the aminoacid tryptophane which is metabolized into serotonin, an active cellsignaling and neurotransmitter molecule. Cytomedines comprise a broaderclass of ligands that interact with cellular receptors to evoke abiological response.

[0039] Benefits have also been reported for the administration oftocotrienols or tocopherols for therapy of cardiovascular disease.Compositions of this invention including active agents such asamiodarone, persantine or adenosine in tocol-based emulsions may beuseful for bolus or IV drip infusion as a vascular tonic in thetreatment of myocardial infarction or for oral administration.

[0040] Where it is desirable to shift the partition coefficient so thatmore of the drug is contained in an oil phase, for example for slowrelease, the teachings of the present invention offer a useful solution.By delivering the active compound in the form of an emulsion, therelease time of the active compound in the blood or tissue can beextended. Reducing the peak concentration (C_(max)) for the free aminecan minimize or modulate systemic or non-specific toxic or adverseevents.

[0041] Other lipophilic active ingredients can be included in thecompositions of this invention, so as to provide additional orcomplementary effects to the active ingredient present as part of thetocol-soluble ion pair. For instance if the active ingredient of the ionpair is a chemotherapeutic or oncolytic agent, the composition maycontain other chemotherapeutics that are soluble or that can besolubilized in tocols, such as qmonafide, illudin S,6-hydroxymethylacylfulvene, bryostatin 1, 26-succinylbryostatin 1,palmitoyl rhizoxin, penclomedine, interferon-alpha, angiogenesisinhibitor compounds, cisplatin hydrophobic complexes such as2-hydrazino-4,5-dihydro-1H-imidazole with platinum chloride and5-hydrazino-3,4-dihydro-2H-pyrrole with platinum chloride, vitamin A,vitamin E and its derivatives, particularly tocopherol succinate,vinblastine, 5-fluorouracil, methotrexate, edatrexate, muramyltripeptide, muramyl dipeptide, lipopolysaccharides,9-β-d-arabinofuranosyladenine (“vidarabine”) and its 2-fluoroderivative.

[0042] Other useful therapeutic agents for inclusion in thetocol-soluble ion pairs of this invention may be selected on the basisof their amphiphilicity and charge as a function of pH, by theirpartition coefficient in buffer:octanol, or by their tocol solubility.As an operative definition, preferred candidates are those for whichtocol solubility can be shown experimentally to increase in the presenceof an ion pair forming compound by measuring drug solubility in thetocol oil with and without the ion-pair. For screening, we have preparedthe free base of a drug with an amine functionality and dissolved thefree base and vitamin E succinate directly in tocopherol with heat. Inother cases we have used ethanol or another volatile co-solvent toinitially dissolve the active agent and its ion pair in a tocol, andthen evaporated the ethanol. Ion pairs that are not soluble in the tocolof choice readily precipitate or crystallize by these methods. Limits ofsolubility may also be established by preparing a series of samplescontaining increasing amounts of the compound in a constant molar massof tocol. After direct dissolution, or after evaporation of residualethanol or other volatile solvent used as a co-solvent, the criticallimit of solubility (S_(c)) of the compound in the tocol of choice canbe determined with accuracy.

[0043] Relatively non-volatile co-solvents such as PEG-400, benzylbenzoate, benzyl alcohol, glycerol, glycerol-, propylene glycol- andpolyethylene glycol-based esters (oils) that are commercially availableunder different trade names such as Capmul® MCM (glycerylmono-/di-caprylate/caprate), Captex® 355 (caprylic/capric triglyceridesfrom coconut oil), Captex® 200 (propylene glycol dicaplylate/dicaprate),Labrafil® M1944 (primarily oleic acid polyglycolyzed glycerides fromapricot kernel oil), Labrasol® (caprylate/caprate polyglycolyzedglycerides from coconut oil), Myvacet® (distilled acetylatedmonoglycerides), Lauroglycol® (propylene glycol mono-/di-laurate),propylene essential lipids (as in U.S. Pat. No. 5,716,928) such asallspice berry, fennel, amber essence, anise seed, arnica, balsam ofPeru, basil, bay leaf, parsley, peanut, benzoin gum, bergamot, rosewood,cajeput, marigold, camphor, caraway, cardamon, carrot, cedarwood,celery, chamomile, cinnamon, citronella, palm oils, sage, clove,coriander, cumin, cypress, eucalyptus, aloe, fennel, fir, frankincense,garlic, geranium, rose, ginger, lime, grapefruit, orange, hyssop,jasmine, jojoba, juniper, lavender, lemon, lemongrass, marjoram,mugwort, watercress, mullen, myrrh, bigarde neroli, nutmeg, bitterorange, oregano, patchouly, pennyroyal, primrose, retinols, papaya,pepper, peppermint, poppyseed, petitegrain, pine, poke root, rosehip,rosemary, sandalwood, sassafras, spearmint, spikenard, hemlock,tangerine, tea tree, thyme, vanilla, banana, coconut, vetivert,wintergreen, witch hazel, ylang ylang extract, or synthetic analogs,also β-carotene, carotenoids, quinones, menadiones, lycopene, crownethers, tributyrin, 1-methyl-2-pyrrolidinone, dimethylsulfoxide,polyvinylalcohol, polyvinylpyrrolidinone, phenol, cholesterol,astaxanthins, phospholipids, polyoxyethylated phospholipids, secondarytocols, Amifat® P30 (glyceryl monopyroglutamate monooleate), surfactantssuch as Cremophor® EL (polyoxyethylated castor oil), Poloxamer 407®,also lnown as Pluronic® F-127 (polyoxyethylene/polyoxypropylenecopolymer), lecithin, bile acids, palmitoyl camitine, fatty acids,Transcutol® (diethylene glycol monoethyl ether) and mixtures thereof,can be used in the compositions of this invention.

[0044] For use in forming ion pairs with cationic drugs, the preferredmethod is to select one or more charged derivatives of a tocol from thelist: vitamin E succinate (VESA), vitamin E phosphate, and other chargedtocopherol esters, amino acid derivatives such as tocopherol aspartateand glutamate, and other tocopherol ester or amide derivatives such asthose disclosed herein or by Senju Pharmaceuticals (U.S. Pat. No.5,606,080 or PCT WO 99/22818). For example, tocopherol succinate as thefree acid (anionic) can be used to complex clarithromycin or amiodaroneas the free base (cationic) to form a tocol-soluble neutral ion pair. Inan oil phase of low dielectric constant, these ion pairs are highlystable once formed. Other tocol-soluble ion pair forming compoundsinclude C₂-C₂₅ tocol-soluble carboxylic acids (preferably the fattyacids) such as acetic, propionic, butyric, valeric, valproic, caprylic,caproic, lauric, myristic, palmitic, oleic, palmitoleic, stearic,linoleic, linolenic, arachidic and arachidonic acid; and include C₂-C₂₅acyl amines such as stearylamine, alkyl phosphates such as decyl andhexadecyl phosphate, other charged lipids such as cholesterol analogs,particularly cholesterol esters such as cholesterol sulfate andcholesterol hemisuccinate and succinate, bile acids, phospholipids suchas phosphatidic acid, phosphatidylserine, phosphatidylglycerol anddiphosphatidylglycerol (cardiolipin), phosphatidylinositol,sphingolipids such as sphingomyelin, cationic lipids such as,N-[1-(2,3-dioleoyloxy]-N, N,N-trimethylammonium chloride (DOTMA),N-L-arginylphosphatidyl-ethanolamine, and 1,2-Diacetyl-3-dimethyl-andtrimethyl-ammonium propane, retinoids, vitamin A, D or K esters, andcharged biosurfactants such as the Amisoft® line of glutamates availablefrom Ajinomoto (Tokyo, Japan) and ascorbyl palmitate.

[0045] In the case of anionic drugs, a preferred composition containstocopheramine. Other positively charged ion pair candidates includestearylamine and sphingomyelin.

[0046] In the case of zwitterionic drugs, more ingenuity is required,but it is well within the scope of this invention to use multiplycharged species so as to neutralize the polarity of the target molecule.For example, esterified fatty acids such as glutamyl stearate can beused to pair with drugs containing both an anionic and cationicfunctional group.

[0047] The compositions of the current invention may be emulsions,microemulsions, self-emulsifying systems, liposomal and niosomaldispersions, gels or liquid crystalline mesophases or their precursors.The preferred forms of the invention are oil-in-water emulsions,microemulsions and self-emulsifying drug delivery systems for oral orparenteral administration of an active agent. Examples of multiphasicsystems having two or more phases include oil-in-water and water-in-oilemulsions and microemulsions, and multiple emulsions of theoil-in-water-in-oil and water-in-oil-in-water structure.

[0048] Therapeutic applications of the formulations envisaged hereinclude the delivery of drugs effective in the treatment of cancer,pain, infections, atherosclerosis, kidney disease, for suppression ofrejection of transplanted organs, and for other medical arts.

[0049] Specific embodiments of this invention are described herein.However, variations and modifications of these embodiments can beeffected without further inventive step, within the teachings and scopeof the invention as described herein.

EXAMPLES Example 1

[0050] Tocol-Soluble Ion Pair Formulation of Clarithromycin forIntravenous Administration.

[0051] Clarithromycin is a macrolide antibiotic widely prescribed for avariety of bacterial infections. Other important members of this classof drugs include azithromycin and erythromycin. Macrolide antibioticsare primarily given orally, although intravenous dosing is indicated insome cases. Macrolides are known for causing venous irritation/pain oninjection, so they are generally given in dilute (2 mg/mL) solutions byslow infusion (total daily doses can be in gram quantities).

[0052] Clarithromycin free base is poorly water soluble but can besolubilized in water as a water-soluble salt, for example thelactobionate or glucoheptonate, solutions of which display theaforementioned venous irritation. The relative lipophilicity ofclarithromycin has led various investigators to propose a variety oflipid dispersed systems, such as liposomes, mixed micelles, andoil-in-water (o/w) emulsions which might shield the drug from contactwith sensitive tissues at the injection site. To date, however, none ofthese has advanced as far as clinical development.

[0053] In particular, the amino group can be exploited throughlipophilic ion pairing to capture the drug in the oil phase of an o/wemulsion. Lovell et al; (1994), Less-painful intravenous administrationof clarithromycin, Int. J. Pharmaceutics 109: 45-57, developed atriglyceride emulsion using fatty acids as lipidic counterions, whichdisplayed roughly a two-fold reduction in pain response in the animalmodels chosen.

[0054] Clarithromycin was obtained as the free base from Wockhardt(Delhi, India). Vitamin E Succinate (VESA) was obtained from Eastman(Freeport Tenn.). Capmul® MCM was obtained from Abitec (JanesvilleWis.); Poloxamer® 407 (Pluronic® F-127) from BASF (Parsippany N.J.);PEG-400 from Spectrum Chemicals (Gardenia Calif.), and d-δ-tocopherolfrom Sigma Chemicals (St Louis Mo.). An oil phase consisting ofd-δ-tocopherol and Capmul MCM was prepared using 2 parts ofδ-tocopherol. Surfactant and clarithromycin were then added as shown inthe table below. Dry ethanol was used to dissolve the components at 70°C. and the ethanol was then removed under vacuum. A clear amber oilresulted, but upon cooling, oblong, “casket-lid” crystals ofclanithromycin were observed. A tocol-soluble ion pair of this compoundwas then produced by addition of a stoichiometric equivalent of VitaminE succinate (VESA) as the free acid. On re-dissolution in ethanol andcooling no crystals formed. The clarithromycin was now sufficientlysoluble in the tocopherol oil to allow subsequent preparation of theemulsion. The oil was then re-heated to 45° C. and degassed immediatelyprior to emulsification as described below. Weight in Final ComponentOil Phase Percent (%) d-δ-tocopherol 2.53 gm 5.0% Capmul MCM 1.28 gm2.5% Poloxamer 407 2.98 gm 3.0% Clarithromycin 0.53 gm 0.5% Vitamin ESuccinate 0.45 gm 0.9%

[0055] The aqueous phase, consisting of 40 mL of 5 mM citrate TEAbuffer, pH 6.8, was brought to 45° C. before addition to the oil phase.Upon addition, the resultant mixture was mixed vigorously to loosen anyadherent oll on the walls of the flask. This suspension was then placedin a vessel and processed in a C5 homogenizer (Avestin, Ottawa Calif.)for 3 min with continuous recycling. Processing conditions were 45° C.feed temperature, 20 kpsi processing pressure and 120 mL/min flow rate.A heat exchanger set at 22° C. was placed at the exit port to removeexcess heat generated in the homogenizer. The temperature in the feedvessel was measured at 44° C. during steady state homogenization.Following processing, the emulsion was collected and cooled to roomtemperature. It was then terminally sterilized by filtration through a0.2 μm filter and had a mean droplet diameter of less than 52 nm whenmeasured on a Nicomp 370 photon correlation spectrophotometer (ParticleSizing Systems, Santa Barbara Calif.).

[0056] Similar emulsions can be made for other lipophilic drugs thatexist as a free base, for example doxorubicin or erythromycin.Optionally, other oils as discussed earlier in the specification andpreferably Lauroglycol® may be used in place of Capmul MCM in theformulation. Miglyol 812 (caprylic/capric triglycerides) and like oilsmay also be used.

Example 2

[0057] Stability of Clarithromycin Formulation

[0058] The physical and chemical stability of the formulation of Example1 at 4° C. was followed for 6 months. No detectable physical change inthe microemulsion incorporating a tocol-soluble ion-pair could bedetected by gross examination or by measuring emulsion droplet sizeusing standard particle sizing methods. Likewise, no detectabledegradation of clarithromycin could be detected by HPLC. In contrast, asolution of the lactobionate salt had degraded by about 50% over thesame time period. Thus, the microemulsion when stored at 4° C. remainedstable for at least 6 months.

Example 3

[0059] Amiodarone as a Tocol-Soluble Ion Pair Compound

[0060] Amiodarone is a Class III anti-arrhythmic for care of patientssuffering or at risk of heart attack. Since 1977, it has beenadministered as an aqueous solution of the HCl salt in 10% Tween 80 and2% benzyl alcohol under the tradename Cordarone® IV.

[0061] Amiodarone was purchased as the HCl salt (Sigma Chemicals, StLouis Mo.). The free base was prepared by dissolving the drug inchloroform and washing the organic phase with saturated sodiumbicarbonate. The drug in the organic phase was then recovered as a paleyellow oil. An emulsion containing 12 mg/mL amiodarone as the free basewas then formulated as follows: Weight in Final Percent Component OilPhase (%) d,1-a-tocopherol  1.0 gm 2.0% TPGS  1.6 gm 3.2% Poloxamer 4070.25 gm 0.5% Amiodarone (free base)  0.6 gm 1.2% Vitamin E Succinate 0.5 gm 1.0% PEG-400  3.0 gm 6.0% Buffer to pH 5.0 qs to 50 mL

[0062] The formulation uses a molar equivalent of amiodarone as the freebase and Vitamin E succinate as the free acid to form the tocol-solubleion pair in the tocol oil before processing. Following homogenization at47° C. for 5 min, a translucent microemulsion was obtained with a meanparticle size of 71 nm. Other anions that are therapeutic for heartdisease, for example the free fatty acids linolenate, eicosapentaenoateor docosahexaenoate from castor oil, were also useful as tocol-solubleion pairs with amiodarone and can be used in the form of an oral drugsupplement for maintenance therapy.

[0063] Mice were then dosed with emulsified amiodarone versus thecommercially available amiodarone solution (Cordarone IV, WyethLaboratories). Before use, Cordarone was diluted 1:5 with 5% dextrose inwater for injection. Animals receiving the commercial solution at 100mg/kg lost coordination, mobility, and experienced prolonged respiratorydisturbance. At an equivalent dose, the emulsion was tolerated muchbetter than the commercially available solution.

Example 4

[0064] Effect of Formulation on Amiodarone Blood Pool Levels

[0065] Amiodarone as the free base was formulated in an emulsion (A)with tocopherol phosphate and was compared with amiodarone HCl withTween 80 and benzyl alcohol as a free solution (B). The comparisoninvolved injection of mice with equal amounts of the drug in a bolusvolume, and then sacrificing the mice at T=6 hr to determine the bloodlevels of drug by HPLC. The data demonstrate that blood levels ofemulsified drug fall more slowly than those of free or solubilized drug,suggesting that the emulsion composition is present as a blood pool andmay have improved therapeutic effect. Treatment (n = 6) Blood Level(μg/mL) A 4.79 ± 1.37 B 1.35 ± 0.41

[0066] Significant levels of drug metabolites in the animals treatedwith solubilized amiodarone HCl were detected, but low levels in animalstreated with emulsion. This suggests that hepatic uptake in the case ofthe soluble form of drug is a principal cause of the low blood levels,and that the liver is responsible for the rapid clearance from bloodfollowed by the appearance of metabolites in blood. Becausehepatotoxicity is a major concern with this drug, the results presentedin this invention suggest a benefit from the use of an emulsifiedformulation of amiodarone.

Example 5

[0067] Relative Release Rates for Amiodarone HCl Versus AmiodaroneTocol-Soluble Ion Pair in a Diffusion Chamber Model

[0068] Amiodarone HCl and a tocol emulsion containing amiodarone andtocopherol phosphate as a tocol-soluble binary ion pair, prepared asmentioned above, were dialyzed against 20% glycerol, 3% Poloxamer 407 atpH 7.4 and 37° C.

[0069] The rate of free or complexed drug exiting the dialysis chamberprovides an indirect estimate of the “sustained release” properties ofthe emulsion and the stfrength of the ion pair species. Rates ofdialysis were linear with concentration for Amiodarone HCl, whereasdiffusion for the amiodarone:tocopherol phosphate ion pair wasnegligible at the highest concentration tested. Given the low dielectricconstant of the oil phase, this suggests the formation of a stable ionpair in the tocol emulsion.

Example 6

[0070] Tocotrienol Formulation for Vitamin E Succinate Co-Therapy

[0071] Given the potential therapeutic effect of Vitamin E succinic acid(VESA) in conjunction with xenotocols for the treatment of breast cancerand other cancers, there is a special need for multiphasic formulationsthat contain VESA in a tocotrienol oil. Here “vehicle” is taken in itscustomary meaning among pharmaceutical formulators to indicate the agentthat carries the drug, the base formulation and excipients, particularlythe oil phase thereof, without consideration of the active drug itself.

[0072] VESA and d-γ-tocotrienol were obtained from Eastman and thetocotrienol was further purified by vacuum distillation at about 30milliTorr and 210° C. A final emulsion of 20 mg/mL VESA in 50 mg/mL ofd-γ-tocotrienol and 12.5 mg/mL Capmul MCM as an oil phase was preparedusing 30 mg/mL Poloxamer 407 as surfactant. PEG-400 was added to a finalconcentration of 5% before emulsification. Emulsification is performedas described in Examples 1 or 4, but may be more rapidly completed byincreasing the temperature of emulsification to 70° C. or higher.Optionally, tocopheramine as the free base may be used to emulsify thisoil mixture at lower temperature.

Example 7

[0073] Erythromycin Emulsion Compositions.

[0074] Erythromycin (free base) solubility in α-tocopherol andmedium-chain triglycerides (MCT) was determined to be approximately 10%and 4% w/w, respectively. Examples of emulsions incorporatingerythromycin that were successfully prepared are shown in the tablebelow.

[0075] Emulsions were prepared as described above. Emulsions A, B, C,and D were homogenized on the C5 to achieve microemulsions that weretranslucent and readily filter-sterilizable through a 0.2 μm membrane.The mean particle diameters of formulations A, B, and D were 47 nm, 48nm, and 81 nm, Emulsion E was processed with the Virtis Handishear toproduce a particle size of approximately 1.7 μm, and emulsion F wasformed by simple stirring. All emulsions and microemulsions showed nosign of any crystallization or drug precipitation when examined visuallyand with a light microscope. Erythromycin emulsion examples Component AB C D E F Component Function (Weight %) Erythromycin Active 0.5 0.5 1.01.3 2.5 2.0 Vitamin E Ion pair 0.5 1.0 1.0 1.8 11.5 Succinate formingCompound α-Tocopherol Oil/Solvent 8.0 8.0 8.0 7.1 MCT Oil/Solvent 25.03.5 TPGS Surfactant 5.0 5.0 5.0 4.5 5.0 3.5 Poloxamer 407 Surfactant 1.01.0 1.0 0.9 Water Aqueous q.s. q.s. q.s. q.s. q.s. q.s. Phase

Example 8

[0076] Conversion of Doxorubicin HCL to Free Base

[0077] Doxorubicin HCl in 8:1 CHCl₃:MeOH produced a drug suspension uponstirring under a stream of gaseous NH₃. The resulting suspension wassubsequently filtered to remove the insoluble material leaving behind ared solvent solution. It was subsequently dried down to a solid freebase with an approximate recovery of 90% based on HPLC without anyevidence of drug degradation.

Example 9

[0078] Tocol-Soluble Doxorubicin Ion Pair Formation and EmulsionComposition

[0079] Vitamin E phosphate is supplied commercially as the sodium salt,so extraction into chloroform with acidic water was necessary to get thefree acid, which was used to make an ion pair with doxorubicin free baseat 2:1 molar ratio, which was soluble in vitamin E. This oil phase, whencombined with the surfactant Tagat® TO (PEG-25 glyceryl trioleate), wasreadily emulsified at 60° C. with water by hand mixing to make a crudeemulsion of the composition shown below with no evidence of drugprecipitation. A fine emulsion can be prepared using high pressurehomogenization to reduce particle size. Component mg/mL Doxorubicin(free base) 0.3 Vitamin E Phosphate 0.6 Vitamin E 23.0 Tagat TO 23.8Water qs

Example 10

[0080] Alternative Doxorubicin Ion-Pairs and Emulsion Compositions

[0081] Using procedures analogous to those of Examples 8 and 9 ion-pairsof doxorubicin with vitamin E succinate, oleic acid, decyl and hexadecylphosphates can be formned and incorporated in α-tocopherol emulsions. Inaddition to vitamin E and TPGS, poloxamers, polysorbates, lecithin,triglycerides, propylene glycol and polyethylene glycol can be included.Emulsion and drug stability can be controlled by optimizing thesurfactant:ion pair:oil phase ratio.

Example 11

[0082] Tocopherolsuccinate-Aspartate

[0083] Tocopherolsuccinate-aspartate is a novel compound that can beused to form ion pairs with cationic pharmaceutically active compoundsused in this invnetion. Synthesis of the tocopherolsuccinate aspartateconjugate was carried out via the use of mixed anhydride chemistry.D-α-tocopherol succinate was activated by adding 1.2 equivalents ofisobutylchloroformate (IBCF) and 1.4 equivalents of N-methylmorpholine(NMM) in a tetrahydrofuran (THF) medium at −5° C. To insure completeconversion to the mixed anhydride the reaction was stirred for 1 hourallowing the mixture to slowly warm to room temperature. The mixedanhydride was filtered to remove the N-methylmorpholine hydrochloridesalt (NMM>HCl). The resulting filtrate was added drop-wise over 45minutes to a −5° C. solution of 1.0 equivalence of L-aspartic aciddibenzyl ester p-toluenesulfonate salt and 1.5 equivalence oftriethylamine (TEA) in THF solution over 1 hour. The reaction wasallowed to continue for an additional 1 hr at −5° C., then warm to roomtemperature and was stirred for an additional 15 hours before isolatingthe product.

[0084] Once the reaction was complete, the THF was removed in a vacuo toyield a crude yellow sticky solid. The product was dissolved indichloromethane (DCM) and washed with 2×0.1 N HCl, 1×Sat. NaHCO₃, and1×Sat. NaCl. The resulting organic mixture was dried over MgSO₄ andremoved in a vacuo to yield an off white solid.

[0085] The tocopherolsuccinate-aspartate dibenzyl ester was deprotectedby hydrogenation to yield the free diacid product. Total yield=72%.Purity=95%+ by HPLC analysis. FT-IR: [N—H (amide), C═O (ester), C═O(amide), and C—O (ether) stretch] are 3336, 1736, 1645, 1153 cm⁻1,respectively. The structure of tocopherolsuccinate-aspartate wasconfirmed by LC-MS.

Example 12

[0086] Tocopherolsuccinate-Glutamate

[0087] Using the methodologies of Example 11, the novel compoundtocopherolsuccinate-glutamate can readily be synthesized andcharacterized.

We claim:
 1. A pharmaceutical composition comprising a tocol as asolvent, and a tocol soluble ion pair comprised of a chargedpharmaceutically active compound or a charged precursor of apharmaceutically active compound, and a compound of opposite chargecapable of forming a tocol-soluble ion pair with the pharmaceuticallyactive compound or precursor.
 2. A composition according to claim 1wherein the tocol is a tocopherol or tocotrienol.
 3. A compositionaccording to claim 1 wherein the tocol is a tocopherol.
 4. A compositionaccording to claim 3 wherein the tocopherol is α-tocopherol.
 5. Acomposition according to claim 3 wherein the tocopherol is β-, γ- orδ-tocopherol.
 6. A composition according to claim 1 wherein the tocol isa tocotrienol.
 7. A composition according according to claim 1, whereinthe tocol is selected from 6-hydroxy,2,5,7,8-tetramethylchroman-2-carboxylic acid and its desmethyl analogs.8. A composition according to claim 1 wherein the pharmaceuticallyactive compound or precursor is selected from pharmaceutically activebases, acids, and natural and synthetic polyelectrolytes, and precursorsthereof.
 9. A composition according to claim 8 wherein thepharmaceutically active compound or precursor is selected frompharmaceutically active carboxylic acids, polycarboxylic acids, amines,polyamines, peptides, polypeptides, proteins, nucleotides,polynucleotides, saccharides, polysaccharides and chargedpolyelectrolytes, and precursors thereof.
 10. A composition according toclaim 9 wherein the pharmaceutically active compound or precursor isselected from pharmaceutically active amines, peptides and polypeptides,and precursors thereof.
 11. A composition according to claim 10 whereinthe pharmaceutically active compound is a macrolide antibiotic or aprecursor thereof.
 12. A composition according to claim 11 wherein themacrolide antibiotic is erythromycin or clarithromycin or a precursorthereof.
 13. A composition according to claim 11 wherein thepharmaceutically active compound or precursor is an anti-arrhythmic drugor a precursor thereof.
 14. A composition according to claim 13 whereinthe anti-arrhythmic drug is amiodarone or a precursor thereof.
 15. Acomposition according to claim 10 wherein the pharmaceutically activecompound or precursor is an anthracycline antibiotic or a precursorthereof.
 16. A composition according to claim 15 wherein theanthracycline antibiotic is doxorubicin, daunorubicin, epirubicin or aderivative thereof, or a precursor thereof.
 17. A composition accordingto claim 10 wherein the pharmaceutically active agent or precursor ismitomycin, bleomycin or an analog thereof, or a precursor thereof.
 18. Acomposition according to claim 10 wherein the pharmaceutically activecompound or precursor is vincristine, vinblastine, a nitrogen mustard,nitrosourea, an analog thereof, or a precursor thereof.
 19. Acomposition according to claim 10 wherein the pharmaceutically activecompound or precursor is camptothecin, an analog thereof or a precursorthereof.
 20. A composition according to claim 19 wherein thepharmaceutically active compound is camptothecin, topotecan, irenotecan,a derivative thereof, or a precursor thereof.
 21. A compositionaccording to claim 10 wherein the pharmaceutically active compound orprecursor is a quinolone antibiotic or a precursor thereof.
 22. Acomposition according to claim 21 wherein the quinolone antibiotic isciprofloxacin, clinafloxacin, levofloxacin, moxifloxacin or a precursorthereof.
 23. A composition according to claim 10 wherein thepharmaceutically active compound or precursor is a biogenic amine or aprecursor thereof.
 24. A composition according to claim 23 wherein thebiogenic amine is histamine, serotonin, epinephrine, an analog thereof,or a precursor thereof.
 25. A composition according to claim 1 inwherein the ion pair forming compound is selected from tocolderivatives, C₂-C₂₅ fatty acids , alkyl phosphates, lipids,phospholipids, retinoids, benzoquinones and esters of Vitamin A, D andK.
 26. A composition according to claim 25 wherein the ion pair formingcompound is a tocol derivative.
 27. A composition according to claim 26wherein the ion pair forming compound is a charged ester ofα-tocopherol.
 28. A composition according to claim 27 wherein thecharged ester is selected from tocopherol acetate, phosphate, succinate,aspartate, and glutamate and mixtures thereof.
 29. A compositionaccording to claim 26 in which the ion pair forming compound is selectedfrom amines of tocopherols and derivatives thereof.
 30. A compositionaccording to claim 29 wherein the ion pair forming compound istocopheramine.
 31. A composition according to claim 1 wherein the ionpair forming compound is selected from C₂-C₂₅ carboxylic acids, C₂-C₂₅amines and mixtures thereof.
 32. A composition according to claim 31wherein the ion pair forming compound is selected from acetic,propionic, butyric, valeric, valproic, caprylic, caproic, lauric,myristic, palmitic, oleic, palmitoleic, stearic, linoleic, linolenic,arachidic and arachidonic acids, and mixtures thereof.
 33. A compositionaccording to claim 31 wherein the ion pair forming compound isstearylamine.
 34. A composition according to claim 25 wherein the ionpair forming compound is selected from charged lipids, phospholipids,sphingolipids and mixtures thereof.
 35. A composition according to claim34 wherein the ion pair forming compound is a cholesterol analog or amixture of cholesterol analogs.
 36. A composition according to claim 35wherein the ion pair forming compound is selected from cholesterolsulfate, cholesterol hemisuccinate, cholesterol succinate and mixturesthereof.
 37. A composition according to claim 34 wherein the ion pairforming compound is a phospholipid or a mixture of phospholipids.
 38. Acomposition according to claim 37 wherein the ion pair forming compoundis selected from phosphatidic acid, phosphatidylserine,phosphatidylinositol, phosphatidylglycerol and diphosphatidylglycerol,and mixtures thereof.
 39. A composition according to claim 34 whereinthe ion pair forming compound is a sphingolipid or mixture ofsphingolipids.
 40. A composition according to claim 39 wherein the ionpair forming compound is selected from sphingosine, phosphatide analogsof sphingosine, and mixtures thereof.
 41. A composition according toclaim 39 wherein the ion pair forming compound is sphingomyelin.
 42. Acomposition according to claim 1 wherein the pharmaceutically activecompound is cationic and the ion pair forming compound is anionic.
 43. Acomposition according to claim 42 wherein the ion pair forming compoundis a succinate or phosphate derivative of a tocopherol.
 44. Acomposition according to claim 42 wherein the pharmaceutically activecompound is selected from erythromycin, clarithromycin, amiodarone,doxorubicin and cationic analogs thereof.
 45. A composition according toclaim 43 wherein the ion pair forming compound is selected fromtocopherol succinate, tocopherol phosphate and mixtures thereof.
 46. Acomposition according to claim 1 wherein the pharmaceutically activecompound is anionic and the ion pair forming compound is cationic.
 47. Acomposition according to claim 46 wherein the pharmaceutically activecompound is a peptide, peptide mimetic, polypeptide, nucleotide orpolynucleotide.
 48. A composition according to claim 46 wherein the ionpair forming compound is tocopheramine, stearylamine, or sphingomyelin.49. A composition according claim 1 in the form of a multiphase system.50. A biphasic composition according to claim
 49. 51. A compositionaccording to claim 49 in the form of an emulsion or microemulsion.
 52. Acomposition according to claim 49 comprising micelles, mixed micelles,reverse micelles, liposomes, niosomes and mixtures thereof.
 53. Acomposition according to claim 49 comprising an oil-in-water orwater-in-oil emulsion or microemulsion.
 54. A composition according toclaim 49 comprising an oil-in-water-in oil or water-in-oil-in-wateremulsion or microemulsion.
 55. A composition according to claim 49further comprising one or more surfactants, one or more co-solvents andone or more aqueous phases.
 56. A composition according to claim 1 inthe form of a self-emulsifying drug delivery system.
 57. A process forsolubilizing in an oil phase a charged pharmaceutically active compoundor a charged precursor thereof comprising combining the pharmaceuticallyactive compound or precursor with an oppositely charged compound capableof forming a tocol-soluble ion pair with the pharmaceutically activecompound or precursor, and with a tocol as a solvent for the ion pair.58. A process according to claim 57 in which the oil phase is an oilphase of a multiphase system.
 59. Tocopherolsuccinate-aspartate. 60.Tocopherolsuccinate-glutamate.
 61. A compositon according to claim 1wherein the ion pair forming compound is tocopherolsuccinate-aspartate.62. A composition according to claim 1 wherein the ion pair formingcompound is tocopherolsuccinate-glutamate.
 63. Pharmaceutical use ofcompositions of claim 1 by administration to an animal or human.